WO1997010842A1

WO1997010842A1 - COMBINATION OF β-INTERFERON FOR THE TREATMENT OF PROSTATE CANCER

Info

Publication number: WO1997010842A1
Application number: PCT/EP1996/004079
Authority: WO
Inventors: Torsten Strohmeyer
Original assignee: Schering Aktiengesellschaft
Priority date: 1995-09-19
Filing date: 1996-09-17
Publication date: 1997-03-27
Also published as: AU7130696A

Abstract

The invention relates to the use of a β-interferon. The β-interferon is suitable for producing drugs for treating prostate cancer. The β-interferon is administered to patients, whose PSA value (prostate specific antigen value) is increased in relation to preceding PSA values.

Description

Use of an interferon-ß for the treatment of prostate cancer

The present invention relates to the use of an interferon-β for the manufacture of a medicament for the treatment of prostate cancer. The invention is based on the priority-based applications DE 195 36 593.3 (filing date September 19, 1995) and DE 195 36 818.5 (filing date September 21, 1995), which were filed with the German Patent Office in Germany.

State of the art prostate

Prostate carcinoma is a malignant, metastatic, inoperable carcinoma. Prostate cancer is only occasionally and partially androgen dependent.

A largely prostate cancer-specific tumor marker is the prostate-specific antigen (PSA), which demonstrably increases in the serum as the tumor progresses. This PSA value is described in the literature in S. BARNETT et al. (1993) Annais of Internal Medicine, Vol 119, No. 9. (Nov. 1, 1993) pp 914 and J.E. OESTERLING (1991) J. Ural. Vol. 145: pp 907-927. It is the only tumor-associated marker in prostate cancer that is reliably detectable, occurs in almost all prostate cancer patients and correlates with the stage of the disease. The PSA marker has been known in the clinic since 1980. His relation to tumor progression has always been conscious. (B.C. KRAMER et al. (1993) Annais of Internal Medicine Vol. 119, 914 in conjunction with L.D. PAPSIDERO et al. (1980) Cancer Res. Vol. 40: 2428-2432)

interferon

The nomenclature used in Nature, Vol. 286, p 2421 (1980) for the group of interferons should be used. Two classes of interferons are known. Class I interferons are small, acid-stable glycoproteins that

Make cells resistant to viral infections. The class II interferons are acid labile. Three groups of interferons are known: interferon-α, interferon-ß and interferon-γ.

The structure of interferon-β with respect to the DNA sequence and the amino acid sequence is described in European patent application EP-0 028 033. Interferon-ß shows biological activity in glycosylated or unglycolysed form. (W.E. STEWART et al. (1979) Virology Vol. 97: 473-476). Interferon-ß is usually not detectable in normal or healthy cells. Only when these cells are exposed to interferon-ß inducers is the interferon-ß expressed. Viruses are usually good interferon-β inducers, but non-viral inducers are also known (S. BARON and F. DIANZANI (eds.) (1977) Texas Reports on Biology and Medicine, 35: ("Texas Report"), pp 526-540.

In addition to human interferon-ß, derivatives are known which are distinguished by the exchange of amino acids. For example, a recombinant interferon-β is described in European patent application EP 0 218 825, which has a serine in position 17 instead of a cysteine. This modification also has biological activity.

A further, modified, human interferon-β is known which has a deletion in position 1, a substitution in position 17 by serine and a non-existing glycosylation. This substance is also biologically active.

Human interferon has long been used successfully in the treatment of some viral infections and cancers. Surprisingly, interferon-ß has not shown any remarkable effect in the treatment of prostate cancer.

In MA BULBUL et al. (1986) J Surg Oncol Vol. 33: 231-233 describes the use of a combination of human fibroblast interferoπ, which corresponds to interferon-ß, and a hormone for the clinical treatment of prostate cancer. Patients were treated first with hormones and then with interferon-ß. The administrations were found to have a very limited effect. CPA

Even before useful antiandrogens were available, DORFMANN postulated that systemically active antiandrogens could be of great benefit in the therapy of androgen-dependent prostate tumors. A multicenter, controlled study at the end of the 1970s, taking into account rational inclusion criteria and differentiated follow-up studies, clearly confirmed that therapy with, for example, cyproterone acetate, which is considered a standard antioxidant, is a good and advantageous alternative to other palliative methods in the treatment of prostate Represents takarcinoma.

Object of the invention

It is an object of the invention to offer the use of an interferon-β in tumor therapy in which a certain patient potential is treated.

Solution of the task

The object is achieved by the use of at least one interferon-β for the manufacture of a medicament for the treatment of a patient with prostate cancer, the patient having a PSA value (prostate-specific antigen value) which is opposite the normal PSA level is increased.

The normal PSA value can be determined relatively and individually by a patient or by an average value which is defined as non-pathological or pathological.

A PSA value which is pathologically increased is preferred. It is more preferred to measure a PSA value relatively in the same patient. It is not the increase compared to the average of the population that is decisive, but rather the increase in the individual PSA value in a patient.

It is known that IFN-ß has no or only insignificant effects in people with extensive prostate cancer. (MA BULBUL et al. (1986) J Surg Oncol Vol. 33: 231 - 233) As a rule, a significantly increased PSA value can be demonstrated in such patients. However, treatment with IFN-ß was unsuccessful. The PSA value had been known since 1980, and thus also in the studies by BULBUL.

In contrast, however, cell models in vitro show that IFN-ß does indeed have a therapeutic effect.

Thus there were conflicting results that could be interpreted in different ways. Targeted technical action cannot be derived from previous publications.

Surprisingly, it was found that when treating prostate cancer with the help of interferon-β, the tumor can only be effectively treated if the patient is being treated primarily at a time when the PSA value is relatively increasing. Continued therapy makes sense. The PSA value is increased compared to the normal value or base value. Treatment is preferably carried out at a point in time at which the PSA value shows a change in the increase. The first increase in the PSA value compared to the normal value or base value is the preferred time at the start of the therapy according to the invention.

On the other hand, it is known from the prior art to treat prostate carcinomas which could be identified by classic diagnostic methods with interferon-ß. The methods can consist of X-ray diagnostics, CT, ultrasound and others. However, only the treatment of the "micrometastases" allows realistic treatment success.

Area-wide use of interferon-β for the treatment of prostate cancer is preferred, with men having the PSA value routinely determined from the age at risk. An increase in the relative PSA value is easy to determine, so that a therapy according to the invention can be initiated.

However, it is more preferred to use IFN-β according to the invention for prostate cancer treatment in patients whose testosterone production has previously been reduced by castration or by drug treatment. After a previously successful anti-hormonal prostate cancer treatment, such patients show a progression of the tumor disease after about two to three years. The PSA value of such patients is good monitor Tumor progress in patients who are closely monitored is usually manifested by an increase in PSA

It is preferred to administer the drug especially during the increase in the PSA value. It is more preferred to continue the treatment with the drug even after this period by passing on the drug

The invention further comprises an interferon-β, which is the human interferon-β or a derivative thereof

The various modified, biologically active interferons show that the change in one or more amino acids does not necessarily lead to a failure or a change in the function. Thus, the term recombinant interferon-ß encompasses both the sequence and the glycosylation of human interferon-ß and Interferon-β-Derivatives All the modifications which lead to a change in the amino acid sequence are included in the derivatives, provided that these modifications include the substitutions, the deletions and / or the insertions of up to 15 amino acids. Deletions, substitutions and / or are preferred Insertions of up to 10 amino acids, more preferably of up to 6 amino acids, most preferably the deletions, substitutions and / or insertions of one, two, three, four or five amino acids

Preferred is the use of an interferon-ß, which is a derivative of human interferon-ß and wherein the derivative a) comprises all modifications of the human interferon, which modifications lead to a change in the amino acid sequence, at least one, at most 15 Amino acids are substituted, deleted or inserted without significantly influencing the activity of the modified interferon-ß compared to the test interferon-ß and b) includes all post-translational modifications that do not significantly affect the activity of the active modified interferon-ß compared to the Affect test interferon-ß

More preferred is the use of an interferon-β in which at most 10 amino acids are substituted, deleted or inserted, without the To significantly influence the activity of the modified interferon-ß compared to the test interferon-ß

The use of an interferon-ß in which at most 6 amino acids are substituted, deleted or inserted is very preferred without significantly influencing the activity of the modified interferon-ß compared to the test interferon-ß

Even more preferred is the use of an interferon-ß in which one, two, three, four or five amino acids are substituted, deleted or inserted, without the activity of the modified interferon-ß compared to the test interferon-ß significantly influence

The use of an unglycosylated or glycosylated interferon-β is more preferred

Most preferred is the use of an interferon-β which is glycosylated and described in EP 0 529 300 (filing date 21 7 92, Siklosi et ai)

The test interferon-ß is an interferon-ß which is unglycosylated, has a substitution in position 17 with senn and a deletion in position 1. This interferon defines the test interferon-ß. A test method is described in T TANIGUCHI et al (1980) Vol 77: 5230-5233 and in DF MARK et al (1984) Vol 81: 5662-5666

Allellic modifications

Most deletions, insertions and substitutions do not appear to result in a radical change in the characteristics of the protein of the invention. Since it is difficult to state in advance the exact effect of a substitution, deletion or insertion, the function of the modified interferon-ß are compared with the function of the modified interferon-ß. The modified, recombinant interferon-ß (test interferon-ß) with the deletion in position 1, the substitution in position 17 by Senn and the lack of glycosylation The genetic code is degenerate, which means that most amino acids are encoded by more than one codon from three nucleotides. Therefore, some allelic modifications at the level of the nucleotides do not lead to a change in the amino acid sequence. Therefore, allelic modifications occur primarily at the DNA level and can have a secondary effect on the amino acid sequence

Amino acids, as shown in Table 1, can be substituted without significantly influencing the function of the protein. In each individual case, the activity test must be used to decide what influence the change has on the function of the protein

The functions or the immunological identity are significantly changed if substituents are chosen which are less conservative in the substitution than the amino acids shown in Table 1. Such substantial changes can be achieved by substitutions with amino acids which are more in their structure and in the Differentiate functional groups Significant changes have the effect that the three-dimensional structure is changed and / or that for example the leaflet structure or the vertical structure is influenced. Interactions between the charges and the hydrophobic chains must also be taken into account in the changes

The mutations are defined by the homology (similartty) of two proteins to be compared. The expression homology includes similar amino acids (for example Table 1) and gaps in the sequences of the amino acids (homology = similanty). The proteins according to the invention have amino acid sequences which have homology of at least 80%, preferably 90%, more preferably 95% and most preferably 98% of the structures according to the invention as defined by the sequence of the recombinant modified interferon-β with Ser ¹⁷ (test-interferon-β) Table 1

Post-translational modifications

The aforementioned post-translational modifications are understood to mean changes that occur during or after translation. Glycosylation, the formation of disulfide bridges, the chemical modifications of the amino acids, such as the sulfation described in connection with hirudin, pay for this ( JW FENTON (1989) 'Thrombin Interactions with Hirudin', Seminars in Thrombosis and Hemostasis Vol 15 265-268)

Glycosylation is an essential function of the endoplasmic reticulum and / or the Golgi apparatus. The sequences and branches of the oligosaccharides are formed in the endoplasmic reticulum and modified in the Golgi apparatus. or O-linked oligosacchands (Senn, threonine or hydroxylysine linked) The form of the glycosylation is dependent on the producing cell type and on the type of the corresponding cell type comes from. The extent and type of glycosylation can be influenced by substances, as described in the European publication EP 0 222 313. Varying glycosylation can alter the function of the protein.

Proteins often form covalent bonds within the chains. These disulfide bridges are made between two cysteines. The protein is folded specifically. The disulfide bridges stabilize the three-dimensional structure of the proteins.

Furthermore, the amino acids can be changed as described in the international publication WO 91/10684. The protein can also be sulfated. This change is described in the context of hirudin.

The invention further preferably comprises the use of an interferon-β which has a proportion of biantennary oligosaccharide structures of at least 60%, a proportion of triantennary oligosaccharide structures of at least 15% and a proportion of tetraantennary oligosaccharide structures 0% to 5% and a sialic acid content of at least 80%.

Also very preferred is the use of an interferon-β which is glycosylated, a proportion of biantennary oligosaccharide structures of at least 60%, a proportion of triatric oligosaccharide structures of at least 15% and a proportion of tetraantennary oligosaccharide structures ren from 0% to 5% and a sialic acid content of at least 80%.

Furthermore, the invention comprises the use of an interferon-β which has a proportion of biantennary oligosaccharide structures of at least 60%, more preferably 70% and most preferably at least 75%.

The invention also comprises the use of an interferon-β which comprises a proportion of triantennary oligosaccharide structures of at least 15%, preferably 20% and most preferably at least 25%. Interferon-β is advantageous, the antenna structures having at least one N-acetyllactosamine repeat.

The antennae structures can be linked 1-4 and / or 1-6. The tetraantennar portion can be 0.5% to 3%.

The invention further comprises the use of an interferon-β which has a sialic acid content of at least 80%, preferably 85% and most preferably more than 90%. The sialic acid component can be composed of N-acetylneuraminic acid and N-glycolylneuraminic acid. The N-acetylneuraminic acid can take up 90-100% and the N-glycolylneuraminic acid 0-10% of the total sialic acid content.

The invention further comprises the use of an interferon-β which has a proportion of fucose content of at least 85%, preferably 90% and most preferably greater than 95%.

The invention further comprises the use of an interferon-β which has at least one oligosaccharide structure with one or more of the following

Formula include:

(i)

Gal ß (1-4) GIcNAc ß (1-2) Man α1

3

Ss (1-4) GIcNAc ß (1-4) GIcNAc 6 |

Gal ß (1 -4) GIcNAc ß (1 -2) Man α1 α (1 -6) Fuc

(ü) Gal ß (1-4) GIcNAc ß (1-2) Man α1

3 NeuAc α (2-3) Man ß (1 -4) GIcNAc ß (1-4) GIcNAc

6 I

Gal ß (1-4) GIcNAc ß (1-2) Man α1 α (1-6) Fuc

(iii)

Gal ß (1 -4) GIcNAc ß (1-2) Man α1

3 [NeuAc α (2-3)] 2 Man ß (1-4) GIcNAc ß (1-4) GIcNAc

6 I

Gal ß (1-4) GIcNAc ß (1-2) Man α1 α (1-6) Fuc (iv)

Gal ß (1 -4) GIcNAc ß (1-2) Man α1

3

Ss (1-4) GIcNAc ß (1-4) GIcNAc 6 I

Gal ß (1-4) GIcNAc ß (1-2) Man α1 α (1-6) Fuc

Gal ß (1 -4) GIcNAc ß (1-6) (v)

Gal ß (1-4) GIcNAc ß (1-4)

Gal ß (1-4) GIcNAc ß (1-2) Man α1

3 Man ß (1 -4) GIcNAc ß (1-4) GIcNAc

6 I

Gal ß (1 -4) GIcNAc ß (1-2) Man α1 α (1-6) Fuc

(vi) Gal ß (1-4) GIcNAc ß (1-2) Man α1

3 NeuAc α (2-3) Man ß (1 -4) GIcNAc ß (1 -4) GIcNAc

6 I

Gal ß (1-4) GIcNAc ß (1-2) Man α1 α (1-6) Fuc

Gal ß (1-4) GIcNAc ß (1 -6)

(vii) Gal ß (1-4) GlcNAc ß (1 -4)

Gal ß (1 -4) GIcNAc ß (1-2) Man α1

3 NeuAc α (2-3) Man ß (1-4) GIcNAc ß (1-4) GIcNAc 6 I

Gal ß (1-4) GIcNAc ß (1-2) Man α1 α (1-6) Fuc

(viii)

Gal ß (1-4) GIcNAc ß (1-2) Man α1 3

[NeuAc α (2-3)] 2 Man ß (1-4) GIcNAc ß (1-4) GIcNAc

6 I

Gal ß (1 -4) GIcNAc ß (1 -2) Man α1 α (1 -6) Fuc

Gal ß (1-4) GIcNAc ß (1-6) (ix)

Gal ß (1 -4) GIcNAc ß (1-4)

Gal ß (1-4) GIcNAc ß (1-2) Man α1 3

[NeuAc α (2-3)] 2 Man ß (1-4) GIcNAc ß (1-4) GIcNAc

6 i

Gal ß (1-4) GIcNAc ß (1-2) Man α1 α (1-6) Fuc (x)

Gal ß (1-4) GIcNAc ß (1-2) Man α1

3 [NeuAc α (2-3)] 3 Man ß (1 -4) GIcNAc ß (1-4) GIcNAc

6 I Gal ß (1-4) GIcNAc ß (1-2) Man α1 α (1-6) Fuc

I.

Gal ß (1-4) GIcNAc ß (1-6)

(xi) Gal ß (1-4) GIcNAc ß (1-4)

I.

Gal ß (1-4) GIcNAc ß (1-2) Man α1

3 [NeuAc α (2-3)] 3 Man ß (1 -4) GIcNAc ß (1-4) GIcNAc 6 |

Gal ß (1 -4) GIcNAc ß (1 -2) Man α1 α (1 -6) Fuc

(xii) [Gal ß (1-4) GIcNAc (1-3)] - *

Gal ß (1-4) GIcNAc ß (1-2) Man α1

3 [NeuAc α (2-3)] 3 Man ß (1 -4) GIcNAc ß (1-4) GIcNAc 6 I

Gal ß (1-4) GIcNAc ß (1-2) Man α1 α (1 -6) Fuc

I.

Gal ß (1-4) GIcNAc ß (1-6) (xiii)

[Gal ß (1-4) GlcNAc (1-3)] - |

Gal ß (1 -4) GIcNAc ß (1-4)

Gal ß (1 -4) GIcNAc ß (1 -2) Man α1

3 [NeuAc α (2-3)] 3 Man ß (1 -4) GIcNAc ß (1 -4) GIcNAc

6 I

Gal ß (1-4) GIcNAc ß (1-2) Man α1 α (1-6) Fuc In the previous formulas, NeuAc can also represent N-glycolylneuraminic acid.

The publication of European patent application EP 0 529 300 (filing date July 21, 1992 with application number 92 112 427.7) describes the previously listed forms of glycosylated interferon-ß in detail and is included in the description by the citation and thereby becomes part of the description.

Combination of compounds with antiandrogenic activity and IFN-ß

It is advantageous to use a combination of (i) at least one compound with antiandrogenic activity and (ii) at least one interferon-β for the manufacture of a medicament for the treatment of a patient with prostate cancer, the patient having a PSA value (prostate-specific - Antigen), which is increased compared to the patient's normal PSA value.

The use of both interferon-ß alone and the combination of interferon-ß and a compound with an antiandrogenic effect also makes sense in patients who have been treated previously or simultaneously with respect to prostate cancer. Such treatment can consist of surgical castration and / or chemical castration, which may be accompanied by antiandrogen treatment.

The following cases are useful: surgical castration and use of interferon - ß; chemical castration and use of interferon - ß;

Use of antiandrogen and interferon - ß; surgical castration and use of antiandrogen and IFN - ß; and chemical castration and the use of antiandrogen and IFN - ß. Antiandrogenic compounds

All compounds which act as competitive antiandrogens, ie. H. those that mediate their anti-drug effects through strong affinity for the androgen receptor. These anti-androgenic compounds can be both steroidal in origin and non-steroids.

The invention comprises the use of a combination according to the invention, the compounds having androgenic activity having the structures of the formula 1 or formula 2:

formula 1

wherein

R ¹ and R2 each represent a hydrogen atom or both together

(i) is a further carbon-carbon bond or (ii) is a methylene group,

R ^{3 represents} the acyl radical of an acid customary in steroid chemistry,

an oxygen atom or the group H or OR ⁴ where R ^{4 is} hydrogen, acyl or alkyl,

X-i represents a hydrogen or chlorine atom and

* 2 represents a hydrogen, fluorine or chlorine atom;

wherein

R5 and R6 each represent hydrogen or both together represent a methylene group, X2 represents hydrogen, fluorine or chlorine and

CH, CH,

AB R ³ - O - C _17a - C ₁₇ = O or O = C _17a - C ₁₇ - O - R ³

mean where

R ^{3 represents} the acyl radical of an acid customary in steroid chemistry. The methyl group of AB points behind the drawing level in the left formula (eight lines before) and in front of the drawing level in the right formula

The term acyl radical should be understood to mean the radicals of the acids customary in steroid chemistry for the esterification of secondary and tertiary hydroxyl groups. Preferred are aliphatic carboxylic acids with 1-8 carbon atoms, such as, for example, acetic acid, propionic acid, butteric acid, valenic acid, isovalenic acid, capronic acid, onanthic acid, etc. The esters of acetic acid are particularly preferred

Alkyl is to be understood as meaning lower alkyl groups with 1-5 carbon atoms, the methyl group being preferred

The invention comprises the use of a combination, the compounds with antiandrogenic activity belonging to the group of the following substances

6-chloro-17-hydroxy-1 α, 2α-methylene-pregna-4,6-dιen-3,20-dιon, 6-chloro-17-hydroxy-pregna-4,6-dιen-3,20-dιon , 6-chloro-17-hydroxy-pregna-1, 4,6-trιen-3,20-dιon, 6-chloro-3ξ, 17-dιhydroxy-1 α, 2α-methyien-pregna-4,6-dιen- 20-one,

6-chloro-3ξ-methoxy-17-hydroxy-1α, 2α-methylene-pregna-4,6-dιen-20-one 6-fluoro-17-hydroxy-1α, 2α-methylene-pregna-4,6-dιen -3,20-dιon, 17-hydroxy-1 α, 2α-methylene-pregna-4,6-dιen-3,20-dιon and 4,6-dιchlor-17-hydroxy-1 α, 2α-methylene-pregna -4,6-dιen-2, 20-dιon

Preferred compounds of the general formula I are

6-chloro-17-hydroxy-1α, 2α-methylene-pregna-4,6-dιen-3,20-dιon-acetate (cyproterone acetate) and 6-chloro-17-hydroxy-pregna-4,6-dιen-3 , 20-dion-acetate

(Chloromadinone acetate)

Typical compounds of the general formula II are for example

6-chloro-17αß-acetoxy-17aα-methyl-1 α, 2α-methylene-D-homo-4,6-androstadιen-3,17-dιon and

6-chloro-17α-acetoxy-17ß-methyl-1 α, 2α-methylene-D-homo-4,6-androstadιen-3, 17a-dιon The steroid pyrazoles and triazoles described in patent applications EP-A-0 207 375 and WO-A-92/00992 are also suitable, for example the (5α, 17α) -1 '- (methylsulfonyl) -I Η-pregn-20 -yno- (3,2-c) -pyrazol-17-ol;

4, 17α-dimethyl-1 '-mesyl-1 Η-androst-4-eno [3,2-c] -pyrazole-17ß-ol; 1 '-Mesyl-17α-methyl-1' H-androsta-4, 15-dieno [3,2-c] -pyrazole-17ß-ol; 6,6-ethylene-1 '-mesyl-17α-methyl-1 Η-androst-4-eno [3,2-c] pyrazol-17ß-ol; 7α, 17α-dimethyl-1 '-mesyl-1 Η-androst-4-eno [3,2-c] -pyrazole-17ß-ol; 2'-Mesyl-17α-methyl-2Η-triazolo [4 ', 5': 2,3] -androsta-4,15-dien-17ß-ol.

Use of IFN-ß or the combination of IFN-ß and a compound with an antiandrogenic effect

The invention includes the use of an interferon-ß alone or the combination of IFN-ß and a compound with antiandrogenic activity, which comprises the pharmacological auxiliary substances and carriers which are physiologically compatible. (Interferon-ß or the combination of IFN-ß and a compound with antiandrogenic activity = substance)

Pharmacological excipients and carriers are ^tn ed in Remington's Pharmaceutical Science, 15., Mack Publishing Company Easton PA (1980). The weight ratio of the substance according to the invention can be varied within wide limits when used for the indication described.

The invention further comprises the use of a substance, the patient having a PSA value (prostate-specific antigen value) which is at least 10%, preferably at least 20%, more preferably at least 30, compared to the normal PSA value % is increased.

Like other serum parameters, the PSA value is subject to fluctuations that are determined by the lifestyle and the daily rhythm. Both physical and psychological reasons can cause a fluctuation around an average and within a fluctuation range. The invention comprises the use of a substance, the PSA value being diagnosable extracorporeally.

The use of a substance is more preferred, the PSA value being diagnosable in a blood sample.

The invention further provides

(i) a method for the treatment of prostate carcinoma, the method comprising the administration of an amount of substance according to the invention, the amount suppressing the disease, and the amount of substance being given to a patient in need of such a medication and having a PSA value which is higher than the patient's normal PSA;

(ii) a pharmaceutical composition for the treatment of prostate cancer, which treatment comprises a substance according to the invention and at least one pharmaceutically acceptable carrier and additive, the patient having a PSA value which is higher than the patient's normal PSA value.

Interferon-ß alone

The suitable dose for this therapeutic effect is different and depends, for example, on the interferon-β, the host, the type of administration and the type and severity of the conditions to be treated.

In general, however, satisfactory results can be expected in larger mammals, for example humans, at daily doses of 10 ⁴ to 10 ⁸ units of interferon-β.

Values of 10 ⁵ to 4 x 10 ⁷ units (interferon-β) per 48 hours are preferred, more preferably 8 x 10 ⁵ to 2 x 10 ⁷ units (interferon-β) per 48 hours and most preferably 3 x 10 ⁶ to 8 x 10 ⁶ units (interferon-ß) per 48 hours.

The active ingredients can be processed with the additives and / or carrier substances customary in galenical pharmacy according to methods known per se to form the usual forms of administration. Ohmic solutions, such as, for example, sesamol or castor oil solutions, are suitable for parenteral administration. To increase the solubility, solution mediators, such as, for example, benzyl benzoate or benzyl alcohol, can be added

In the case of systemic treatment, the interferon-β can be administered in any customary way, in particular injection solutions or suspensions are the corresponding forms for the administration

The use of the modified interferon-β according to EP 0 529 300 is the particularly preferred combination. It is administered, for example, in the case of larger mammals, for example humans, in the manner described above. The subcutaneous injection in conventional aqueous solvents, for example physiological saline solution, is for the preferred form of administration for systemic treatment

Combination of interferon-ß and a compound with antiadrogenic

effect

In general, however, satisfactory results can be expected for larger mammals, for example humans, at daily doses of 10 ⁴ to 10 ⁸ units of interferon-β and 1 to 500 mg of cyproterone acetate or an equivalent amount of another antiandrogen

Values of 10 ⁵ to 4 × 10 ⁷ units (interferon-β) per 48 hours and 50 to 500 mg (antiandrogen) per day are preferred, more preferably 8 × 10 ⁵ to 2 × 10 ⁷ units (interferon-β) per 48 Hours and 50 to 500 mg (antiandrogen) per day and most preferably 3 x 10 ⁶ to 8 x 10 ⁶ units (interferon-ß) per 48 hours and 50 to 500 mg (antiandrogen) per day

The combination can be administered simultaneously or at different times

The active ingredients can be processed with the additives, carrier substances and / or flavoring agents customary in galenical pharmacy according to methods known per se to form the usual forms of administration

Tablets, coated tablets, capsules, pills, suspensions or solutions are particularly suitable for oral administration For parenteral administration, oily solutions such as e.g. B. sesame oil or castor oil solutions, suitable. To increase the solubility, solubilizers, such as. As benzyl benzoate or benzyl alcohol can be added.

With regard to the antiandrogen in systemic treatment, the combination can be administered in any conventional way, preferably orally. Suppositories, tablets, capsules, drops, solutions for injection or suspensions are the appropriate forms for administration.

With regard to interferon-β according to EP 0 529 300, the combination can be administered in any conventional way in the case of systemic treatment, in particular injection solutions or suspensions to be injected subcutaneously are the corresponding forms for the administration.

The combination of modified interferon-β according to EP 0 529 300 and the antiandrogen cyproterone acetate is the particularly preferred combination. It is used, for example, in larger mammals, e.g. B. humans, administered in the manner shown above. The infusion solution as a continuous infusion in conventional aqueous solvents, e.g. B. physiological saline, is the preferred form of administration for systemic treatment.

Example:

(i). IFN-ß alone

The first clinical trial was started in May 1996. At the moment (3.9.1996) 14 patients are being treated, 60 patients will take part in the study. The study is carried out in the Federal Republic of Germany.

(i). (i). Patient

Patients are selected who have asymptomatic, progressive prostate cancer that can no longer be controlled by hormones alone. Furthermore, the patients show an increase in the PSA concentration, which is determined by blood tests.

(i). (ii). IFN-ß

IFN-ß is used as the drug, which is IFN-ß 1a and a

Structure according to publication EP 0 529 300 (Siklosi et al., Filing date on

July 21, 1992).

The injections contain 0 μg, 5 μg, 15 μg or 30 μg interferon-ß 1a, which corresponds to 0 MU, 1 MU, 3 MU or 6 MU (mega-units).

The wording looks like this:

The formulation is taken up in 1 ml of distilled water. The interferon-ß is injected subcutaneously three times a week in three dose groups of 1, 3 and 6 MU (mega units). A placebo serves as control, in which only the interferon - ß 1a is missing.

(i) - (iü). PSA value

According to the publication by S. BARNETT et al. (1993) Annais of Internal Medicine, Vol. 119, No. 9: pp 914-922 measured. there blood samples are taken from the patients every four weeks. A test kit from Abbott, which is commercially available, is preferably used for the measurement.

(ii). IFN-ß and antiadrogenic compound

The combination of interferon and an antiandrogen is described in the planned test below.

(ii). (i). Approaches to CPA (ii). (I). (I). Approach 1

The composition of an antiandrogenic tablet for oral administration

The tablet is manufactured in the usual way on a tablet press. If appropriate, the active compounds according to the invention, each with half of the additives indicated above, can also be pressed separately into a two-layer tablet.

(ii) - (i) - (ü) - Approach 2

Composition of another antiandrogenic tablet for oral administration

(ii). (i). (iii). Approach 3

For the injection of cyproterone acetate, an oily solution is made by mixing 50 mg of cyproterone acetate with 353 mg of castor oil and 618 mg of benzyl benzoate. This results in 1071 mg, which take up the volume of one milliliter.

(ii). (i). (iv). Approach 4

For the composition of an interferon-ß injection cf. (i). (ii).

(ii). (ii). Patient

see. (i). (i).

(ii). (iii). PSA value

The PSA value is determined according to (i). (Iii). measured.

The test substance cyproterone acetate is dissolved in benzyl benzoate + castor oil (compare approach 3) and the single dose of 50 mg per day s.c. or p.o. applied. When used orally, the test substance is suspended in a carrier liquid (85 mg myrj in 100 ml 0.9% w / v NaCl solution) and the daily dose is administered. The test substance interferon-ß is in the form of (i). (Ii). sprayed.

51318AWOM1XX00-P 9/16/1996

Claims

claims

1. Use of at least one interferon-ß for the production of a

Medicament for the treatment of a patient with prostate carcinoma, the patient having a PSA value (prostate-specific antigen value) which is higher than the normal PSA value.

2. Use of an interferon-ß according to claim 1, wherein the interferon-ß is a derivative of human interferon-ß and wherein the derivative a) includes all modifications of human interferon-ß, which modifications to a change in the amino acid - Lead sequence, wherein at least one, at most 15 amino acids are substituted, deleted or inserted, without the activity of the modified interferon-ß compared to the test

To significantly influence interferon-ß and b) includes all post-translational modifications which do not significantly affect the activity of the active modified interferon-ß compared to the test interferon-ß.

3. Use of an interferon-ß according to any one of the preceding claims, wherein the interferon-ß is unglycosylated or glycosylated.

4. Use of an interferon-β according to claim 3 which is unglycosylated, has a substitution in position 17 with serine and a deletion in position 1.

5. Use of an interferon-β according to claim 3, which has a proportion of biantennary oligosaccharide structures of at least 60%, a proportion of tnantennary oligosaccharide structures of at least 15% and a proportion of tetraantennary oligosaccharide structures from 0% to 5% and has a sialic acid content of at least 80%.

6. Use of an interferon-ß according to any one of the preceding claims, wherein the interferon-ß pharmacological auxiliaries and Träger¬ substances that are physiologically acceptable.

7. Use of an interferon-β according to one of the preceding claims, wherein the patient has a PSA value (prostate-specific ant value) which is increased by at least 10% compared to the normal PSA value.

8. Use of an interferon-ß according to one of the preceding claims, wherein the PSA value can be diagnosed extracorporeally.

9. Use of an interferon-ß according to claim 8, wherein the PSA value can be diagnosed in a blood sample.

10. Use of a combination of (i) at least one compound with antiandrogenic activity and (ii) at least one interferon-ß according to any one of the preceding claims for the manufacture of a medicament for the treatment of a patient with prostate cancer, wherein the

Patient has a PSA (prostate-specific-antigen value), which is higher than the patient's normal PSA value.